UCH-L1 Inhibition Suppresses tau Aggresome Formation during Proteasomal Impairment
In conditions of proteasomal impairment, the damaged or misfolded proteins, collectively known as aggresome, can accumulate in the perinuclear space and be subsequently eliminated by autophagy. Abnormal aggregation of microtubule-associated protein tau in the cytoplasm is a common neuropathological feature of tauopathies. The deficiency in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, is closely related to tau aggregation; however, the associated mechanisms remain unclear. Here, we showed that UCH-L1 inhibition interrupts proteasomal impairment-induced tau aggresome formation. By reducing the production of lysine (K63)-linked ubiquitin chains, UCH-L1 inhibition decreases HDAC6 deacetylase activity and attenuates the interaction of HDAC6 and tau protein, finally leading to tau aggresome formation impairment. All these results indicated that UCH-L1 plays a key role in the process of tau aggresome formation by regulating HDAC6 deacetylase activity and implied that UCH-L1 may act as a signaling molecule to coordinate the effects of the ubiquitin-proteasome system and the autophagy-lysosome pathway, which mediate protein aggregates degradation in the cytoplasm.
KeywordsUbiquitin carboxy-terminal hydrolase L1 Tau aggresome K63-linked ubiquitin chains Histone deacetylase 6
We thank Professor Wang Jianzhi at the Tongji Medical College of Huazhong University of Sciences and Technology, Wuhan, China for providing the HEK293/tau441 cell line used in this study. This work was financially supported by the Nature Science foundation of Hubei Province (No. 2016CFB561), the project of Hubei Key Laboratory of Genetic Regulation and Integrative Biology (Grant No. GRIB201604), and the National Natural Science Foundation of China (No. 31372212).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 6.Wang Y, Martinezvicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2010) Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy 6(1):182–183. doi: 10.4161/auto.6.1.10815 CrossRefPubMedGoogle Scholar
- 15.Tan JMM, Wong ESP, Kirkpatrick DS, Pletnikova O, Han SK, Tay SP, Ho MWL, Troncoso J et al (2008) Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum Mol Gen 17(3):431–439. doi: 10.1093/hmg/ddm320 CrossRefPubMedGoogle Scholar
- 31.Bilguvar K, Tyagi NK, Ozkara C, Tuysuz B, Bakircioglu M, Choi M, Delil S, Caglayan AO et al (2013) Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc Natl Acad Sci U S A 110(9):3489–3494. doi: 10.1073/pnas.1222732110 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Castegna A, Aksenov M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002) Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part II: Dihydropyrimidinase-related protein2, α-enolase and heat shock cognate71. J Neurochem 82(6):1524–1532. doi: 10.1046/j.1471-4159.2002.01103.x CrossRefPubMedGoogle Scholar
- 33.Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem 279(13):13256–13264. doi: 10.1074/jbc.M314124200 CrossRefPubMedGoogle Scholar
- 34.Minjarez B, Valero Rustarazo ML, Mm SDP, González-Robles A, Sosa-Melgarejo JA, Luna-Muñoz J, Mena R, Luna-Arias JP (2013) Identification of polypeptides in neurofibrillary tangles and total homogenates of brains with Alzheimer's disease by tandem mass spectrometry. JAD 34(1):239–262. doi: 10.3233/JAD-121480 PubMedGoogle Scholar